Farnesyl transferase inhibiting 6-heterocyclylmethyl quinolinone derivatives

ABSTRACT

This invention comprises the novel compounds of formula (I)  
                 
 
     wherein r, t, y 1 —y 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

[0001] The present invention is concerned with novel6-heterocyclylmethyl quinolinone derivatives, the preparation thereof,pharmaceutical compositions comprising said novel compounds and the useof these compounds as a medicine as well as methods of treatment byadministering said compounds.

[0002] Oncogenes frequently encode protein components of signaltransduction pathways which lead to stimulation of cell growth andmitogenesis. Oncogene expression in cultured cells leads to cellulartransformation, characterized by the ability of cells to grow in softagar and the growth of cells as dense foci lacking the contactinhibition exhibited by non-transformed cells. Mutation and/oroverexpression of certain oncogenes is frequently associated with humancancer. A particular group of oncogenes is known as ras which have beenidentified in mammals, birds, insects, mollusks, plants, fungi andyeasts. The family of mammalian ras oncogenes consists of three majormembers (“isoforms”): H-ras, K-ras and N-ras oncogenes. These rasoncogenes code for highly related proteins generically known asp21^(ras). Once attached to plasma membranes, the mutant or oncogenicforms of p21^(ras) will provide a signal for the transformation anduncontrolled growth of malignant tumor cells. To acquire thistransforming potential, the precursor of the p21^(ras) oncoprotein mustundergo an enzymatically catalyzed farnesylation of the cysteine residuelocated in a carboxyl-terminal tetrapeptide. Therefore, inhibitors ofthe enzymes that catalyzes this modification, i.e. farnesyl transferase,will prevent the membrane attachment of p21^(ras) and block the aberrantgrowth of ras-transformed tumors. Hence, it is generally accepted in theart that farnesyl transferase inhibitors can be very useful asanticancer agents for tumors in which ras contributes to transformation.

[0003] Since mutated oncogenic forms of ras are frequently found in manyhuman cancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

[0004] In EP-0,371,564 there are described (1H-azol-1-ylmethyl)substituted quinoline and quinolinone derivatives which suppress theplasma elimination of retinoic acids. Some of these compounds also havethe ability to inhibit the formation of androgens from progestinesand/or inhibit the action of the aromatase enzyme complex.

[0005] In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, thereare described 2-quinolinone and quinazolinone derivatives which exhibitfarnesyl transferase inhibiting activity. WO 00/39082 describes a classof novel 1,2-annelated quinoline compounds, bearing a nitrogen- orcarbon-linked imidazole, which show farnesyl protein transferase andgeranylgeranyl transferase inhibiting activity. Other quinolonecompounds having farnesyl transferase inhibiting activity are describedin WO 00/12498, 00/12499 and 00/47574.

[0006] Unexpectedly, it has been found that the present novel6-heterocyclylmethyl quinolinones compounds show farnesyl proteintransferase inhibiting activity.

[0007] The present invention concerns compounds of formula (I):

[0008] or a pharmaceutically acceptable salt or N-oxide orstereochenucally isomeric form thereof, wherein

[0009] r is 0, 1, 2, 3, 4 or 5;

[0010] t is 0, 1, 2 or 3;

[0011] >Y¹-Y²—is a trivalent radical of formula

>C═CR⁹—  (y-2)

>CH—CHR⁹—  (y-4)

[0012] wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkyloxy, halocarbonyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aryl or a group of formula —NR²²R²³,—C₁₋₆alkyl-NR²²R²³—C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or—NR²²—C₁₋₆alkyl-NR²²R²³;

[0013] p is 0 to 5;

[0014] R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl and areindependently defined for each iteration of p in excess of 1;

[0015] R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or —(CR ²R²)_(p)-C₃₋₁₀cycloalkyl, or together with the adjacent nitrogen atom forma 5- or 6-membered heterocyclic ring optionally containing one, two orthree further heteroatoms selected from oxygen, nitrogen or sulphur andoptionally substituted by one or two substituents each independentlyselected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,aminocarbonyl, mono- or di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonylamino, oxime, or phenyl;

[0016] R¹ is azido, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴SC₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het²C₁₋₆alkyl,—C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³,—C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr², —C₁₋₆alkylNR²²COAr²,C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³, trihalomethoxy,arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio, C₂₋₆alkenyl,cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³, hydroxycarbonylC₂₋₆alkenyl,C₁₋₆alkyloxycarbonyl-C₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl,hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,—CONR²²R²³, —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het²,—CONR²²—C₁₋₆alkyl-Ar², —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl,—NR²²R²³, —OC(O)R²⁴, —CR²³═NR²⁵, —CR²⁴═N—OR²⁵, —NR²⁴C(O)NR²²R²³,—NR²⁴SO₂R²⁵, —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵, —C(NR²⁶R²⁷)═NR²⁸;—Sn(R²⁴)₃, —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵, aryloxy, Het²-oxy,

[0017] or a group of formula

—Z, —CO—Z or —CO—NR^(y)—Z

[0018]  in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5-or 6-membered heterocyclic ring containing one or more heteroatomsselected from oxygen, sulphur and nitrogen, the phenyl or heterocyclicring being optionally substituted by one or two substituents eachindependently selected from halo, cyano, hydroxycarbonyl, aminocarbonyl,C₁₋₆alkylthio, hydroxy, —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyloxy or phenyl; or two R¹ substituents adjacentto one another on the phenyl ring may form together a bivalent radicalof formula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

—O—CH═CH—  (a-3)

—O—CH₂—CH₂—  (a-4)

—O—CH₂—CH₂—CH₂—  (a-5)

—CH═CH—CH═CH—  (a-6)

[0019] R²⁴ and R²⁵ are independently hydrogen, C₁₋₆ alkyl,—CR₂₀R₂₁)_(p)—C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl;

[0020] R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or C(O)C₁₋₆alkyl;

[0021] R² is a mono- or bi-cyclic heterocyclic ring containing either atleast one oxygen heteroatom or two or more heteroatoms selected fromoxygen, sulphur and nitrogen, each such ring being optionallysubstituted by one or two substituents each independently selected fromhalo, cyano, hydroxy, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³,C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³,—NR²²R²³, C₁₋₆alkylsulfonylamino, oxime, phenyl or benzyl;

[0022] R³ is hydrogen, halo, cyano, C₁₋₆alkyl,—(CROR²)_(p)—C₁₀₋₃cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,arylC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl,hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³,arylC₁₋₆alkyl, Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenylNR²²R²³,C₂,alkynyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or

[0023] a radical of formula —O-—R¹⁰ (b-1) —S-—R¹⁰ (b-2) or —NR¹¹R¹²(b-3)

[0024] wherein R¹⁰ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkylcarbonyl, aryl, a group of formula —NR²²R²³R or—C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a radical of formula —Alk-OR¹³ or-Alk-NR¹⁴R¹⁵;

[0025] R¹¹ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;

[0026] R¹² is hydrogen, hydroxy, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group offormula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl,arylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkylmoiety may optionally be substituted by one or more substituentsindependently selected from aryl andC₁₋₆alkyloxycarbonyl substiuents;aminocarbonylcarbonyl, mono- ordi(C₁₋di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula-Alk-OR¹³ or Alk-NR¹⁴R¹⁵;

[0027] wherein Alk is C₁₋₆alkanediyl;

[0028] R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl ,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, aryl orarylC₁₋₆alkyl;

[0029] R¹⁴ is hydrogen,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl ,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;

[0030] R¹⁵ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl ,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl or arylC₁₋₆alkyl;

[0031] R⁴ is a radical of formula

[0032] wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl,—(Cr²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁alkyloxy, C₁₋₆alkylthio, a group of formula—NR²²R²³, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl or aryl, R¹⁷ ishydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl, trifluoromethyl,trifluoromethylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminosulphonyl or—C₁₋₆,alkylP(O)OR²⁴OR²⁵;

[0033] R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³;

[0034] R⁶ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl or—C₁₋₆alkyl-NR²²R²³, R²⁴SO₂, R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴,—C₁₋₆alkyl-SR²⁴, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³,—C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het², —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Ar²,—C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkylCONR²²Ar², —C₁₋₆alkylCONR²²—O—C₁alkyl,—C₁₋₆alkylCONR²²—C₁₋₆alkenyl, -Alk-Ar² or -AlkHet²;

[0035] R⁷ is oxygen or sulphur;

[0036] Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by oneto five substituents each independently selected from halo, hydroxy,cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alyloxy,OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent substituent offormula —O—CH₂—O— or —O—CH₂—CH₂—O—;

[0037] Het² is a mono- or bi-cyclic heterocyclic ring containing one ormore heteroatoms selected from oxygen, sulphur and nitrogen andoptionally substituted by one or two substituents each independentlyselected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl,-alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino,oxime or phenyl.

[0038] As used in the foregoing definitions and hereinafter, halo isgeneric to fluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straightand branched chain saturated hydrocarbon radicals having from 1 to 4carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituentsfor example trifluoromethyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals containing one double bond and having from 2to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term“S(O)” refers to a sulfoxide and “S(O)₂” to a sulfone. Aryl definesphenyl, naphthalenyl or phenyl substituted with one or more substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl, cyano, hydroxycarbonyl.

[0039] The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

[0040] The term acid addition salts also comprises the hydrates and thesolvent addition forms which the compounds of formula (I) are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

[0041] The term stereochemically isomeric forms of compounds of formula(I), as used hereinbefore, defines all possible compounds made up of thesame atoms bonded by the same. sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

[0042] Some of the compounds of formula (I) may also exist in theirtautomeric forms. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

[0043] Whenever used hereinafter, the term “compounds of formula (I)” ismeant to include also the pharmaceutically acceptable acid additionsalts and all stereoisomeric forms.

[0044] Examples of compounds of formula (I) include those wherein one ormore of the following restrictions apply:

[0045] r is 0, 1 or 2;

[0046] t is 0 or 1;

[0047] >Y¹-Y² is a trivalent radical of formula

>C═CR⁹—  (y-2)

[0048] wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxycarbonyl or aminocarbonyl;

[0049] R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonylC₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy,C₁₋₆alkylthio, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, or—CH═NOR²⁵; or two R¹ substituents adjacent to one another on the phenylring may independently form together a bivalent radical of formula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

[0050] R² is a 5- or 6-membered monocyclic heterocyclic ring containingeither one oxygen heteroatom or two or three heteroatoms selected fromoxygen, sulphur and or nitrogen or a 9- or 10-membered bicyclicheterocyclic ring containing either one oxygen heteroatom or two orthree heteroatoms selected from oxygen, sulphur and or nitrogen

[0051] R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,—C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl, —C₂₋₆alkenyl NR²²R²³, or -Het²; or agroup of formula

—O—R¹⁰   (b-1)

—NR¹¹R¹²   (b-3)

[0052] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹³or-Alk-NR¹⁴R¹⁵;

[0053] R¹¹ is hydrogen or C₁₋₆alkyl;

[0054] R¹² is hydrogen, hydroxy, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,aminocarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵;

[0055] wherein Alk is C₁₋₆alkanediyl;

[0056] R¹³ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;

[0057] R¹⁴ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)^(p)—C₃₋₁₀cycloalkyl;

[0058] R¹⁵ is hydrogen or C₁₋₆alkyl;

[0059] R⁴ is a radical of formula (c-2) wherein

[0060] R¹⁶ is hydrogen, halo or C₁₋₆alkyl,

[0061] R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,

[0062] C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl;

[0063] R⁵ is cyano, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy orC₁₋₆alkyloxycarbonyl:

[0064] R is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴,—C₁₋₆alkyl-C(O)NR²²R²³, -Alk-Ar², —AlkHet² or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,

[0065] R⁷ is oxygen; Het² is a 5- or 6-membered monocyclic heterocyclicring containing one, two or three heteroatoms selected from oxygen,sulphur or nitrogen for example pyrrolidinyl, imidazolyl, triazolyl,pyridyl, pyrimidinyl, furyl, morpholinyl, piperazinyl, piperidinyl,thiophenyl, thiazolyl or oxazolyl, or a 9- or 10-membered bicyclicheterocyclic ring especially one in which a benzene ring is fused to aheterocyclic ring containing one, two or three heteroatoms selected fromoxygen, sulphur or nitrogen for example indolyl, quinolinyl,benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl orbenzodioxolanyl.

[0066] A group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

[0067] >Y¹-Y²—is a trivalent radical of formula (y-2), wherein R⁹ ishydrogen, halo, C₁₋₄alkyl, hydroxycarbonyl, or C₁₋₄alkyloxycarbonyl;

[0068] r is 0, 1 or 2;

[0069] t is 0;

[0070] R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one anotheron the phenyl ring may independently form together a bivalent radical offormula (a-1);

[0071] R² is a 5- or 6-membered monocyclic heterocyclic ring containingone oxygen heteroatom or two heteroatoms selected from oxygen, sulphuror nitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which abenzene ring is fused to a heterocyclic ring containing either at leastone oxygen heteroatom or two or heteroatoms selected from oxygen,sulphur or nitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl oraryl;

[0072] R³ is Het² or a group of formula (b-1) or (b-3) wherein

[0073] R¹⁰ is hydrogen or a group of formula -Alk-OR¹³.

[0074] R¹¹ is hydrogen;

[0075] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;

[0076] Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;

[0077] R⁴ is a group of formula (c-2) wherein

[0078] R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;

[0079] R¹⁷ is hydrogen or C₁₋₆alkyl;

[0080] R⁶ is —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴,aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet² or C₁₋₆alkyl;

[0081] R⁷ is oxygen;

[0082] aryl is phenyl.

[0083] A particular group of compounds consists of those compounds offormula (I) wherein >Y¹-Y² is a trivalent radical of formula (y-2), r is0 or 1, t is 0, R¹ is halo, C(₁₋₄)alkyl or forms a bivalent radical offormula (a-1), R² is a 5- or 6-membered monocyclic heterocyclic ringcontaining either one oxygen heteroatom or two heteroatoms selected fromoxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclicring in which a benzene ring is fused to a heterocyclic ring containingeither one oxygen heteroatom or two or heteroatoms selected from oxygen,sulphur or nitrogen, optionally substituted by halo, cyano , C₁₋₆alkylor aryl; R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is aradical of formula (c-2), R¹⁰ is hydrogen or -Alk-OR¹³, R¹² is hydrogenand R¹² is hydrogen or C₁-C₁₋₆alkylcarbonyl and R¹³ is hydrogen; R⁶ isC₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴(R²⁴═H,Et),aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and

[0084] R⁷ is oxygen.

[0085] More preferred compounds are those compounds of formula (I)wherein >Y¹-Y² is a trivalent radical of formula (y-2), r is 0 or 1, sis 1, t is 0, R¹ is halo, preferably chloro and most preferably3-chloro, R² is a furyl, diazolyl, oxazolyl or benzodiazolyl,benzotriazolyl group, optionally substituted by halo preferably chloro,cyano, C₁₋₆alkyl, preferably methyl or aryl; R³ is hydrogen or a radicalof formula (b-1) or (b-3), R⁴ is a radical of formula (c-2), R⁹ ishydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen R⁶ isC₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²; R⁷ is oxygen.

[0086] Especially preferred compounds are those compounds of formula (I)wherein >Y¹-Y² is a trivalent radical of formula (y-2), r is 1, t is 0,R¹ is halo, preferably chloro, and most preferably 3-chloro, R² is a3-furyl, imidazol-1-yl, , benzimidazol-1-yl group optionally substitutedby halo preferably chloro, cyano, C₁₋₆alkyl, preferably methyl orphenyl; R³ is a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-2), R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² ishydrogen or hydroxy, R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or -alkylAr²;and R⁷ is oxygen.

[0087] The most preferred compounds according to the invention are:

[0088](±)-4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,

[0089](±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,

[0090]6-[1H-benzimidazol-1-yl(1-methyl-1H-inidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,

[0091]6-[1H-1,2,3-benzotriazol-1-yl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,

[0092]4-(3-chlorophenyl)-1-methyl-6-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-2(1H)-quinolinone,

[0093]4-(3-chlorophenyl)-6-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,

[0094]4-(3-chlorophenyl)-1-methyl-6-[(1-methyl-1H-imidazol-5-yl)(4-methyl-1H-imidazol-1-yl)methyl]-2(1H)-quinolinone,and their pharmaceutically acceptable salts.

[0095] The compounds of formula (I) and their pharmaceuticallyacceptable salts and N-oxides and stereochemically isomeric formsthereof may be prepared in conventional manner, for example by a processwhich comprises:

[0096] a) cyclising a compound of formula (II)

[0097] with a reagent serving to form a compound of formula (I) in whichR⁶ is hydrogen and R⁷ is oxygen;

[0098] b) reacting a compound of formula (III):

[0099] in which W¹ represents a replaceable or reactive group, with areagent serving either to react with or replace the W¹ group in compound(III) to form a compound of formula (I) in which R⁶ is hydrogen and R⁷is an oxygen or sulphur group; or

[0100] c) reacting a compound of formula (IV):

[0101] in which W² is a leaving group and W³ is the group R² above or W²is the group R⁴ above and W³ is a leaving group, with a reagent servingto replace the leaving group W² or W³ with the respective R⁴ or R²group; or

[0102] d) reacting a compound of formula (V):

[0103] (in which R^(x) is the group R² or R⁴ above) with a heterocyclicreagent of formula R^(4a)L (when R^(x) is R²) or R^(2a)L (when R^(x) isR⁴) in which L is a leaving atom or group and R^(2a) is R² or aprecursor group therefor and R^(4a) is R⁴ or a precursor group therefor,and if required, converting said precursor group to the parent group, toform a compound of formula (I) in which R³ is hydroxy;

[0104] e) reacting a compound of formula (VI):

[0105] with a reagent serving to convert the said compound (VI) to acompound of formula (I) in which R⁶ is hydrogen and R⁷ is oxygen;

[0106] and optionally effecting one or more of the following conversionsin any desired order:

[0107] (i) converting a compound of formula (I) into a differentcompound of formula (I);

[0108] (ii) converting a compound of formula (I) in to apharmaceutically acceptable salt or N-oxide thereof;

[0109] (iii) converting a pharmaceutically acceptable salt or N-oxide ofa compound of formula (I) into the parent compound of formula (I);

[0110] (iv) preparing a stereocherical isomeric form of a compound offormula (I) or a pharmaceutically acceptable salt or N-oxide thereof.

[0111] With regard to process a), this can be effected as described forexample in an analogous manner to that described in WO 97/21701 andWO98/49157 referred to above. Thus, the cyclisation may be effected forexample by subjecting the compound of formula (II) to an acetylationreaction, e.g. by treatment with the anhydride of a carboxylic acid,e.g. acetic anhydride in a reaction-inert solvent, e.g. toluene, andsubsequent reaction with a base such as potassium tert-butoxide in areaction-inert solvent such as 1,2-dimethoxyethane.

[0112] With regard to process b), this can also be effected for examplein an analogous manner to that as described in WO 97/21701 andWO98/49157 referred to above for the preparation of compounds in whichR⁷ is oxygen, for example by hydrolysis of an ether of formula (II) inwhich W¹ is C₁₋₆alkyloxy in an aqueous acid solution such hydrochloricacid Alternatively a compound of formula (III) in which W¹ is a chlororadical can be used.

[0113] With regard to process c), this can be effected for example byN-alkylating an intermediate of formula (IVa), wherein W² is anappropriate leaving group such as, for example, chloro, bromo,methanesulfonyloxy or benzenesulfonyloxy, with an intermediate offormula (VII) to form a compound of formula (I) in which R⁴ is a groupof formula (c-1) represented by compounds of formula (I-a):

[0114] The reaction can be performed in a reaction-inert solvent suchas, for example, acetonitrile, and optionally in the presence of asuitable base such as, for example, sodium carbonate, potassiumcarbonate or triethylamine. Stirring may enhance the rate of thereaction. The reaction may conveniently be carried out at a temperatureranging between room temperature and reflux temperature.

[0115] Also, compounds of formula (I-a) can be prepared by reacting anintermediate of formula (IVb) in which W² is hydroxy with anintermediate of formula (VIII), wherein Y is oxygen or sulfur, such as,for example, a 1,1′-carbonyldiimidazole.

[0116] Said reaction may conveniently be conducted in a reaction-inertsolvent, such as, e.g. tetrahydrofuran, optionally in the presence of abase, such as sodium hydride, and at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture.

[0117] Similar procedures can be used to introduce the R² group using acompound of formula (IV) in which W³ is a leaving group.

[0118] With regard to process d), this.can be used to introduce the R⁴group, for example by reacting a compound of formula (V) in which R^(x)is R² with an imidazole reagent to form a compound of formula (I) inwhich R⁴ is a group of formula (c-2). In more detail, the compounds offormula (I) wherein R⁴ represents a radical of formula (c-2), R³ ishydroxy and R is C₁₋₆alkyl, said compounds being referred to ascompounds of formula (I-b-1) may be prepared by reacting an intermediateketone of formula (Va) with an intermediate of formula (III-1). Saidreaction requires the presence of a suitable strong base, such as, forexample, butyl lithium in an appropriate solvent, such as, for example,tetrahydrofuran, and the presence of an appropriate silane derivative,such as, for example, triethylchlorosilane. During the work-up procedurean intermediate silane derivative is hydrolyzed. Other procedures withprotective groups analogous to silane derivatives can also be applied.

[0119] Also, the compounds of formula (I), wherein R⁴ is a radical offormula (c-2), R³ is hydroxy and R¹⁷ is hydrogen, said compounds beingreferred to as compounds of formula (I-b-2) may be prepared by reactingan intermediate ketone of formula (Va) with a intermediate of formula(III-2), wherein PG is a protective group such as, for example, asulfonyl group, e.g. a dimethylamino sulfonyl group, which can beremoved after the addition reaction. Said reaction is conductedanalogously as for the preparation of compounds of formula (I-b-1),followed by removal of the protecting group PG, yielding compounds offormula (I-b-2). Similar procedures can be used to introduce the R²group by reacting a compound of formula (V) in which R^(x) is R⁴ with aR²L reagent for example a lithium compound.

[0120] With regard to process e), this may be effected for example asdescribed in WO 97/21701 referred to above, by reacting the nitrone offormula (VI) with the anhydride of a carboxylic acid, e.g. aceticanhydride, thus forming the corresponding ester on the 2-position of thequinoline moiety, which ester can then be hydrolysed in situ to thecorresponding quinolinone using a base such potassium carbonate.

[0121] Examples of the interconversion of one compound of formula (I)into a different compound of formula (I) include the followingreactions:

[0122] a) compounds of formula (I-b) can be converted to compounds offormula (I-c), defined as a compound of formula (I) wherein R is aradical of formula (c-2) and R³ is hydrogen, by submitting the compoundsof formula (I-b) to appropriate reducing conditions, such as, e.g.stirring in acetic acid in the presence of formamide, or treatment withsodium borohydride/trifluoroacetic acid.

[0123] b) compounds of formula (I-b) can be converted to compounds offormula (I-f) wherein R³ is halo, by reacting the compounds of formula(I-b) with a suitable halogenating agent, such as, e.g. thionyl chlorideor phosphorus tribromide. Successively, the compounds of formula (I-f)can be treated with a reagent of formula H-NR¹¹R¹² in a reaction-inertsolvent, thereby yielding compounds of formula (I-g).

[0124] c) compounds of formula (I-b) can be converted into compounds offormula (I-g) for example by treatment with SOCl₂, and then NH₃/iPrOH,e.g. in a tetrahydrofuran solvent, or by treatment with acetic acidammonium salt at a temperature ranging from 120 to 180° C., or bytreatment with sulfamide at a temperature ranging from 120 to 180° C.;

[0125] d) compounds of formula (I-f) can be converted into compounds offormula (I-c) for example by treatment with SnCl₂ in the presence ofconcentrated HCl in acetic acid at reflux;

[0126] e) compounds of formula (I) in which >Y¹-Y² represents a radicalof formula or (y-2) can be converted into corresponding compounds offormula (I) in which >Y¹-Y² represents a radical of formula (y-4)respectively, by conventional reduction procedures for examplehydrogenation.

[0127] f) compounds of formula (I) in which X is oxygen can be convertedinto corresponding compounds of formula (I) in which X is sulphur with areagent such as phosphorus pentasulfide or Lawesson's reagent in asuitable solvent such as, for example, pyridine.

[0128] The compounds of formula (I) may also be converted into eachother via art-known reactions or functional group transformations. Anumber of such transformations are already described hereinabove. Otherexamples are hydrolysis of carboxylic esters to the correspondingcarboxylic acid or alcohol; hydrolysis of amides to the correspondingcarboxylic acids or amines; hydrolysis of nitrites to the correspondingamides; amino groups on imidazole or phenyl may be replaced by ahydrogen by art-known diazotation reactions and subsequent replacementof the diazo-group by hydrogen; alcohols may be converted into estersand ethers; primary amines may be converted into secondary or tertiaryamines; double bonds may be hydrogenated to the corresponding singlebond.

[0129] The intermediates and starting materials used in theabove-described processes my be prepared in conventional manner usingprocedures known in the art for example as described in the above-mentioned patent specifications WO 97/16443, WO 97/21701, WO 98/40383,WO 98/49157 and WO 00/39082.

[0130] Compounds of formula (III) in which W¹ is chloro or morepreferably OCH₃, R³ is hydroxy and Y¹-Y² is (y-2), herein referred to ascompounds of formula (IIIa), may be prepared for example by proceduressummarised in the following synthetic Routes A and B:

[0131] Compounds of formula (III) in which W¹ is OCH₃, R³ is hydroxy,and Y¹-Y² is (y-2), herein referred to as compounds of formula (IIIb),may be prepared for example by procedures summarised in the followingsynthetic Route C:

[0132] Compounds of formula (V) in which R^(x) is R⁴ R⁷ is oxygen andY¹-Y² is (y-2), herein referred to as compounds of formula (Vb), may beprepared for example by procedures summarised in the following syntheticRoute D:

[0133] Compounds of formula (IV) in which W² is Cl, W³ is R⁴, R⁷ isoxygen, R³ is H and Y¹-Y² is (y-2), herein referred to as compounds offormula (IVc), may be prepared for example by procedures summarized inthe following reaction scheme E:

[0134] In general in relation to the above Routes A, B and C, the groupsR² and R⁴ can be interchanged, for example, where a R² reagent is usedto introduce the R² group, the corresponding R⁴ reagent canalternatively be employed to introduce the R⁴ group. Thus, when a R²reagent is used to introduce the R² group before the R⁴ group, it ispossible in the alternative to use the corresponding R⁴ reagent tointroduce the R⁴ group before the R² group.

[0135] The compounds of formula (I) and some of the intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration.

[0136] The compounds of formula (I) as prepared in the hereinabovedescribed processes are generally racemic mixtures of enantiomers whichcan be separated from one another following art-known resolutionprocedures. The racemic compounds of formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

[0137] The compounds of formula (I), the pharmaceutically acceptableacid addition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they have a potent farnesyl proteintransferase (FPTase) inhibitory effect.

[0138] This invention provides a method for inhibiting the abnormalgrowth of cells, including transformed cells, by administering aneffective amount of a compound of the invention. Abnormal growth ofcells refers to cell growth independent of normal regulatory mechanisms(e.g. loss of contact inhibition). This includes the abnormal growth of:(1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumorcells in which the ras protein is activated as a result of oncogenicmutation of another gene; (3) benign and malignant cells of otherproliferative diseases in which aberrant ras activation occurs.Furthermore, it has been suggested in literature that ras oncogenes notonly contribute to the growth of tumors in vivo by a direct effect ontumor cell growth but also indirectly, i.e. by facilitatingtumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55,4575-4580, 1995). Hence, pharmacologically targeting mutant rasoncogenes could conceivably suppress solid tumor growth in vivo, inpart, by inhibiting tumor-induced angiogenesis.

[0139] This invention also provides a method for inhibiting tumor growthby administering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma and includingnon-small cell lung cancer), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), hematopoietic tumors of lymphoidlineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt'slymphoma), myeloid leukemias (for example, acute myelogenous leukemia(AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS),tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas),melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor ofthe skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breastcancer), kidney carcinoma, ovary carcinoma, bladder carcinoma andepidermal carcinoma.

[0140] This invention may also provide a method for inhibitingproliferative diseases, both benign and malignant, wherein ras proteinsare aberrantly activated as a result of oncogenic mutation in genes.With said inhibition being accomplished by the administration of aneffective amount of the compounds described herein, to a subject in needof such a treatment. For example, the benign proliferative disorderneurofibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention. The compound according to the invention canbe used for other therapeutic purposes, for example:

[0141] a) the sensitisation of tumors to radiotherapy by administeringthe compound according to the invention before, during or afterirradiation of the tumor for treating cancer, for example as describedin WO 00/01411;

[0142] b) treating athropathies such as rheumatoid arthritis,osteoarthritis, juvenile arthritis, gout, polyarthritis, psoriaticarthritis, ankylosing spondylitis and systemic lupus erythematosus, forexample as described in WO 00/01386;

[0143] c) inhibiting smooth muscle cell proliferation including vascularproliferative disorders, atherosclerosis and restenosis, for example asdescribed in WO 98/55124;

[0144] d) treating inflammatory conditions such as ulcerative colitis,crohn's disease, allergic rhinitis, graft vs host disease,conjunctivitis, asthma, ards, behcets disease, transplant rejection,uticaria, allergic dermatitis, alopecia areata, scleroderma, exanthem,eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis,kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis andchronic bronchitis;

[0145] e) treating endometriosis, uterine fibroids, dysfunctionaluterine bleeding and endometrial hyperplasia;

[0146] f) treating ocular vascularisation including vasculopathyaffecting retinal and choroidal vessels;

[0147] g) treating pathologies resulting from heterotrimeric G proteinmembrane fixation including diseases related to following biologicalfunctions or disorders; smell, taste, light, perception,neurotransmission, neurodegeneration, endocrine and exocrine glandfunctioning, autocrine and paracrine regulation, blood pressure,embryogenesis, viral infections, immunological functions, diabetes,obesity;

[0148] h) inhibiting viral morphogenesis for example by inhibiting theprenylation or the post-prenylation reactions of a viral protein such asthe large delta antigen of hepatitis D virus; and the treatment of HIVinfections;

[0149] i) treating polycystic kidney disease;

[0150] j) suppressing induction of inducible nitric oxide includingnitric oxide or cytokine mediated disorders, septic shock, inhibitingapoptosis and inhibiting nitric oxide cytotoxicity;

[0151] k) treating malaria.

[0152] Hence, the present invention discloses the compounds of formula(I) for use as a medicine as well as the use of these compounds offormula (I) for the manufacture of a medicament for treating one or moreof the above mentioned conditions.

[0153] For the treatment of the above conditions, the compound of theinvention may be advantageously employed in combination with one or moreother anti-cancer agents for example selected from platinum coordinationcompounds for example cisplatin or carboplatin, taxane compounds forexample paclitaxel or docetaxel, camptothecin compounds for exampleirinotecan or topotecan, anti-tumor vinca alkaloids for examplevinblastine, vincristine or vinorelbine, anti-tumor nucleosidederivatives for example 5-fluorouracil, gemcitabine or capecitabine,nitrogen mustard or nitrosourea alkylating agents for examplecyclophosphamide, chlorambucil, carmustine or lomustine, antitumoranthracycline derivatives for example daunorubicin, doxorubicin oridarubicin; HER2 antibodies for example trastzumab; and anti-tumorpodophyllotoxin derivatives for example etoposide or teniposide; andantiestrogen agents including estrogen receptor antagonists or selectiveestrogen receptor modulators preferably tamoxifen, or alternativelytoremifene, droloxifene, faslodex and raloxifene, or aromataseinhibitors such as exemestane, anastrozole, letrazole and vorozole.

[0154] For the treatment of cancer the compounds according to thepresent invention can administered to a patient as described above inconjunction with irradiation; such treatment is may be especiallybeneficial as farnesyl transferase inhibitors can act asradiosensitisers for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

[0155] Irradiation means ionizing radiation and in particular gammaradiation, especially that emitted by linear accelerators or byradionuclides that are in common use today. The irradiation of the tumorby radionuclides can be external or internal.

[0156] Preferably, the administration of the farnesyl transferaseinhibitor commences up to one month, in particular up to 10 days or aweek, before the irradiation of the tumor. Additionally, it isadvantageous to fractionate the irradiation of the tumor and maintainthe administration of the farnesyl transferase inhibitor in the intervalbetween the first and the last irradiation session.

[0157] The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumor, its location, thepatients' reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

[0158] The present invention also concerns a method of cancer therapyfor a host harboring a tumor comprising the steps of

[0159] administering a radiation-sensitizing effective amount of afarnesyl protein transferase inhibitor according to the inventionbefore, during or after

[0160] administering radiation to said host in the proximity to thetumor.

[0161] In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

[0162] To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

[0163] Because of their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit form, in which casesolid pharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment.

[0164] It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

[0165] Those skilled in the art could easily determine the effectiveamount from the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of activeingredient per unit dosage form.

[0166] The following examples are provided for purposes of illustration.

[0167] Experimental Part

[0168] Hereinafter “THF” means tetrahydrofuran, “DIPE” means diisopropylether, “DME” means 1,2-dimethoxyethane, “EtOAc” means ethyl acetate,“DCM” means dichloromethane and “BuLi” means n-butyl lithium.

[0169] A. Preparation of the Intermediates

EXAMPLE A1

[0170] a) Sodium hydroxide (0.62 mol) was dissolved in methanol (100mol) and the mixture was cooled till room temperature.1-bromo-4-nitro-benzene (0.124 mol), followed by3-chloro-benzeneacetonitrile (0.223 mol) were added dropwise, thetemperature raised till 50° C. and the mixture was stirred at roomtemperature for one night. The mixture was poured into water and ice,the precipitate was filtered off, washed with water and extracted withDME and methanol. The organic layer was dried (MgSO₄), filtered off andevaporated till dryness. The residue was taken up in diethylether,filtered off and dried, yielding 13.2 g (34.8%) of5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole, mp. 163° C. (intermediate1).

[0171] b) TiCl₃ (1050 ml) was added at room temperature to a solution ofintermediate (1) (0.386 mol) in THF (1350 ml) and the mixture wasstirred at room temperature for 2 h. The mixture was poured into waterand ice and extracted with DCM. The organic layer was decanted, washedwith K₂CO₃ 10%, dried (MgSO₄), filtered off and evaporated, yielding 102g (85%) of (2-amino-5-bromophenyl)(3-chlorophenyl)-methanone(intermediate 2).

[0172] c) A solution of intermediate (2)(0.328 mol) and acetic acid,anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed forone night. The mixture was evaporated and the product was used withoutfurther purification, yielding 139 g (quant.) ofN-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).

[0173] d) 2-methyl,2-propanol, potassium salt (1.635 mol) was addedportionwise at room temperature to a solution of intermediate (3) (0.328mol) in DME (1200 ml) and the mixture was stirred at room temperaturefor one night. The mixture was evaporated till dryness, the residue waspoured into water and ice and decanted. The oily residue was taken up inDIPE, the precipitate was filtered off, washed with EtOAc, CH₃CN anddiethylether and dried, yielding 88.6 g (80.76%) of6-bromo-4-(3-chlorophenyl)-2(1H)-quinolinone (intermediate 4).

[0174] e) A mixture of intermediate (4)(0.16 mol) in phosphoryl chloride(500 ml) was stirred and refluxed for one night. The mixture wasevaporated till dryness, the residue was taken up in ice and water,alkalized with NH₄OH and extracted with DCM. The organic layer wasdecanted, dried (MgSO₄), filtered off and evaporated, yielding 56 g(100%) 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline, mp. 125° C.(intermediate 5). f)CH₃ONa 30%/CH₃OH (96 mi) was added to a solution ofintermediate (5)(0.16 mol) in methanol (500 ml) and the mixture wasstirred and refluxed for one night. The mixture was evaporated tilldryness, the residue was taken up in DCM, washed with water anddecanted. The organic layer was dried (MgSO₄), filtered off andevaporated. The residue was taken up in diethylether and DIPE, theprecipitate was filtered off and dried, yielding 48 g (86%) of6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline, mp. 124° C. (intermediate6).

[0175] g) BuLi 1.6M in hexane (0232 mol) was added dropwise at −20° C.to a mixture of intermediate (6)(0.0223 mol) in THF (80 ml). The mixturewas stirred at −20° C. for 30 min and added dropwise at −20° C. to amixture of bis(1-methyl-1H-imidazol-5-yl)-methanone (0.0089 mol) in THF(20 ml). The mixture was stirred for 1 hour, hydrolyzed and extractedwith EtOAc. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH90/10/0.5; 15-40 μm). The pure fractions were collected and the solventwas evaporated, yielding 0.20 g (5%) of4-(3-chlorophenyl)-2-methoxy-α,α-bis(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol(intermediate 7).

EXAMPLE A2

[0176] a) BuLi 1.6 M in hexane (0.03 mol) was added dropwise at −78° C.under N₂ flow to a mixture of intermediate (6)(0.0287 mol) in THF (75ml). The mixture was stirred at −78° C. for 15 min. A solution of1-methyl-1H-imidazole-5-carboxaldehyde (0.03 mol) in THF(10 ml) wasadded quickly while the temperature was kept below 50° C. The mixturewas allowed to warm to room temperature, hydrolyzed and extracted withDCM. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (14.2 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1;20-45 μm). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone and DIPE. Theprecipitate was filtered off and dried, yielding 5.3 g of4-(3-chlorophenyl)-2-methoxy-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol,mp. 205° C. (intermediate 8).

[0177] b) KMnO₄(0.0182 mol) was added portionwise at room temperature toa mixture of intermediate (8)(0.018 mol) in2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]-ethanamine (1 ml)and DCM (70 ml). The mixture was stirred at room temperature for 2 hoursand then filtered over celite. The precipitate was washed with DCM. Theorganic solution was washed with water, dried (MgSO₄), filtered and thesolvent was evaporated, yielding 6.8 g (100%) of[4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](1-methyl-1H-imidazol-5-yl)-methanone(intermediate 9).

[0178] c) BuLi 1.6 M in hexane (0.0111 mol) was added dropwise at −70°C. under N₂ flow to a mixture of thiazole (0.0111 mol) in diethyl ether(30 ml). The mixture was stirred at −70° C. for 1 hour. A mixture ofintermediate (9)(0.0074 mol) in THF (30 ml) was added dropwise. Themixture was stirred at −70° C. for 1 hour, hydrolyzed and extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated till dryness. The residue (4 g) was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1; 15-40 μm). The pure fractions were collected and the solventwas evaporated, yielding 3.1 g (91.1%) of4-(3-chlorophenyl)-2-methoxy-α-(1-methyl-1H-imidazol-5-yl)-α-(2-thiazolyl)-6-quinolinemethanol(intermediate 10).

[0179] d) A mixture of intermediate (10)(0.0065 mol) in HCl 3N (100 ml)and THF (100 ml) was stirred and refluxed for 6 hours. The mixture waspoured out on ice, alkalized with a concentrated NH₄OH solution andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated till dryness, yielding 3 g(>100%) of4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-2-thiazolylmethyl]-2(1H)-quinolinone(intermediate 11).

EXAMPLE A3

[0180] a) A mixture of sodium hydroxide (0.64 mol) in ethanol (300 ml)was stirred at room temperature for 15 min.2-(4-nitrophenyl)-1,3-dioxolane (0.128 mol) was added portionwise. Themixture was stirred for 30 min. and 3-chloro-benzene acetonitrile(0.2304 mol) was added. The mixture was stirred at room temperature for3 hours. Ice water was added. The precipitate was filtered off, washedwith water and with ethanol and dried, yielding: 28.47 g (74%) of3-(3-chlorophenyl)-5-(1,3-dioxolan-2-yl)-2,1-benzisoxazole (intermediate12), mp. 160° C.

[0181] b) A mixture of intermediate (12)(0.0941 mol) in HCl 6N (200 ml)and methanol (100 ml) was stirred and refluxed for 6 hours, cooled andpoured out on ice. The precipitate was filtered off, washed with diethylether and dried, yielding 21.8 g (90%) of3-(3-chlorophenyl)-2,1-benzisoxazole-5-carboxaldehyde (intermediate 13),mp. 148° C.

[0182] c) BuLi (0.118 mol) was added dropwise at −70° C. under N₂ flowto a solution of 4-phenyl-thiazole (0.097 mol) in THF (205 ml). Themixture was stirred at −70° C. for 1 hour. A solution of intermediate(13)(0.0692 mol) in THF (205 ml) was added dropwise. The mixture wasstirred at −70° C. for 2 hours, brought to -30° C. over a 90-min period,poured out into NH₄Cl 10% and extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (39.5 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 80/20; 20-45 μm). The pure fractions werecollected and the solvent was evaporated. A part (1.5 g) of the residue(18 g, 62%) was crystallized from 2-propanone. The precipitate wasfiltered off and dried, yielding 1.5 g (84%) of3-(3-chlorophenyl)-α-(4-phenyl-2-thiazolyl)-2,1-benzisoxazole-5-methanol(intermediate 14), mp. 136° C.

[0183] d) A mixture of intermediate (14)(0.0656 mol) and MnO₂ (27.5 g)in 1,4-dioxane (275 ml) was stirred at 80° C. for 3 hours, then cooledto room temperature, filtered over celite and pasted up withCH₂Cl₂/CH₃OH. The solvent was evaporated till dryness, yielding 27.3 g(100%) of[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-phenyl-2-thiazolyl)-methanone(intermediate 15).

[0184] e) TiCl₃ 15% in water (300 ml) was added slowly at roomtemperature to a mixture of intermediate (15)(0.0656 mol) in THF(500ml). The mixture was stirred at room temperature overnight, then pouredout into ice water, extracted with DCM and washed with K₂CO₃ 10%. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness, yielding 25.5 g (92.7%) of[4-amino-3-(3-chlorobenzoyl)phenyl](4-phenyl-2-thiazolyl)-methanone(intermediate 16).

[0185] f) A mixture of intermediate (16)(0.048 mol) in DCM (200 ml) wascooled on an ice bath. 3-chloro-3-oxo-propanoic acid, ethyl ester (0.105mol) was added dropwise. The mixture was stirred at a low temperaturefor 30 min, then stirred and refluxed for 1 hour and poured out intowater. The organic layer was separated, washed with K₂CO₃ 10%, dried(MgSO₄), filtered and the solvent was evaporated till dryness. Theproduct was used without further purification, yielding (quant.)N-[2-(3-chlorobenzoyl)-4-[(4-phenyl-2-thiazolyl)carbonyl]phenyl]-3-oxo-β-alanineethyl ester (intermediate 17).

[0186] g) A mixture of intermediate (17)(0.048 mol) in DME (250 ml) wascooled on an ice bath. and 2-methyl-2-propanol, potassium salt (0.096mol) was added portionwise. The mixture was stirred at a low temperaturefor 15 min, poured out into ice water and acidified with HCl 3N. Theprecipitate was filtered off, washed with water, pasted up with CH₃CNand diethyl ether, then dried, yielding 17.3 g (70%) of ethyl4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(4-phenyl-2-thiazolyl)carbonyl]-3-quinolinecarboxylate(intermediate 18), mp 261° C.

[0187] h) A mixture of intermediate (18)(0.0336 mol) in methanol (100ml) and THF (100 ml) was cooled on an ice bath. Sodium tetrahydroborate(0.0336 mol) was added portionwise. The mixture was stirred at a lowtemperature for 30 min, then poured out into ice water and extractedwith DCM. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue was crystallizedfrom 2-propanone/DIPE. The precipitate was filtered off and dried,yielding 14.2 g (81.6%) of ethyl4-(3-chlorophenyl)-1,2-dihydro-6-[hydroxy(4-phenyl-2-thiazolyl)methyl]-2-oxo-3-quinolinecarboxylate(intermediate 19), mp. 127° C.

[0188] i) Thionyl chloride (30 ml) was added dropwise to a mixture ofintermediate (19) (0.0245 mol) in DCM (150 ml), previously cooled on anice bath. The mixture was stirred at a low temperature for 1 hour and atroom temperature overnight. The solvent was evaporated till dryness. Theproduct was used without further purification, yielding (quant.) ofethyl4-(3-chlorophenyl)-6-[chloro(4-phenyl-2-thiazolyl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate(intermediate 20).

EXAMPLE A4

[0189] a) A mixture of intermediate (8) in HCl 3N (70 ml) was stirred at80° C. for 16 hours, cooled, poured out on ice and basified with aconcentrated NH₄OH solution. The precipitate was filtered off, washedwith water and with diethyl ether, then dried, yielding 5.1 g (95%) of4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinolinone(intermediate 21), mp. 186° C.

[0190] b) A mixture of intermediate (21)(0.0132 mol), iodomethane(0.0264 mol) and benzyltriethylammonium chloride (0.00132 mol) in THF(50 ml) and sodium hydroxide 10 N (50 ml) was stirred at roomtemperature overnight. EtOAc was added. The mixture was decanted. Theorganic layer was dried, filtered and the solvent was evaporated. Theresidue (2.9 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: toluene/2-propanol/NH₄OH70/29/1; 15-40 μm). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from diethyl ether. Theprecipitate was filtered off and dried, yielding 0.45 g of4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,mp. 167° C. (intermediate 22).

[0191] c) A mixture of intermediate (22)(0.0026 mol) in thionyl chloride(10 ml) was stirred at 40° C. for 8 hours. The solvent was evaporatedtill dryness. This product was used without further purification,yielding6-[chloro(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinonehydrochloride (intermediate 23).

EXAMPLE A5

[0192] a) A mixture of (intermediate 6)(0.043 mol) in THF (150 ml) wascooled to −70° C. under N₂ flow. BuLi 1.6 M in hexane (0.056 mol) wasadded dropwise. The mixture was stirred at −70° C. for I hour. A mixtureof 3-furancarboxaldehyde (0.056 mol) in THF(60 ml) was added dropwise.The mixture was stirred at −70° C. for 30 min, hydrolized, extractedwith EtOAc and decanted. The organic layer was dried (MgSO₄), filteredand the solvent was evaporated till dryness. The residue (20 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH99/1; 20-45 μm). The pure fractions were collected and the solvent wasevaporated, yielding 14 g (90%) of4-(3-chlorophenyl)-α-(3-furanyl)-2-methoxy-6-quinolinemethanol(intermediate 24).

[0193] b) A mixture of (intermediate 24)(0.0382 mol) and MnO₂ (28 g) intrichloromethane (200 ml) was stirred and refluxed overnight. Themixture was cooled to room temperature, filtered over celite and thesolvent was evaporated till dryness. The product was used withoutfurther purification, yielding 11.5 g (82.7%) of[4-(3-chlorophenyl)-2-methoxy-6-quinolinyl]-3-furanyl-methanone(intermediate 25).

[0194] c) A mixture of (intermediate 25)(0.0434 mol) in THF (160 ml) andHCl 3N (160 ml) was stirred and refluxed overnight. The mixture waspoured out into ice water and alkalized with a concentrated NH₄OHsolution. The precipitate was filtered off, washed with water and dried,yielding 15 g (98.7%) of4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-2(1H)-quinolinone (intermediate26), melting point >250° C.

[0195] d) A mixture of (intermediate 26)(0.04 mol) in DMF (200 ml) wascooled to 5° C. under N₂ flow. NaH 80% in oil (0.048 mol) was addedportionwise. The mixture was stirred at 5° C. for 30 min. Theniodomethane (0.048 mol) was added dropwise. The mixture was stirred at5° C. for 30 min, hydrolized and poured out into water. The precipitatewas filtered off, washed with water and taken up in CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue (15.5 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/EtOAc 85/15; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue (13.3 g, 91.7%) was crystallized from CH₃CN and DIPE. Theprecipitate was filtered off and dried, yielding 1.5 g (9.6%) of4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-1-methyl-2(1H)-quinolinone(intermediate 27), melting point 192° C.

EXAMPLE A6

[0196] a) A mixture of intermediate 4 (0.045 mol), iodomethane (0.225mol) and benzyltriethylammonium chloride (0.0045 mol) in NaOH (150 ml)and THF (150 ml) was stirred overnight. EtOAc was added. The mixture waswashed with water. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated till dryness. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc;95/5; 20-45 μm). The pure fractions were collected and the solvent wasevaporated, yielding 13.5 g (86%) of6-bromo-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (intermediate 28),melting point 182° C.

[0197] b) A mixture of (intermediate 28)(0.066 mol),1-methyl-5-(tributylstannyl)-1H-imidazole (0.121 mol) and Pd(PPh₃)₄(0.0066 mol) in triethylamine (23 ml) and dioxane (230 ml) was stirredat 90° C. overnight under a 5 bar pressure of carbon monoxide, thencooled, poured out into ice water and extracted with EtOAc. The mixturewas filtered over celite and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated,yielding fraction 1 (organic layer). Celite was washed withCH₂Cl₂/CH₃OH. The solvent was evaporated, yielding fraction 2. Fraction2 was washed with diethyl ether, filtered off and dried under a vacuo,yielding 17.6 g (70%) of4-(3-chlorophenyl)-1-methyl-6-[(1-methyl-1H-imidazol-5-yl)carbonyl]-2(1H)-quinolinone(intermediate 29).

[0198] B. Preparation of the Final Compounds

EXAMPLE B1

[0199] A mixture of intermediate (7)(0.00141 mol) in HCl 3N (20 ml) andTHF (5 ml) was stirred and refluxed overnight. The solvent wasevaporated till dryness. The product was used without furtherpurification, yielding 0.73 g (quant.) of4-(3-chlorophenyl)-6-[hydroxybis(1-methyl-1H-imidazol-5-yl)methyl-2(1H)-quinolinonehydrochloride (1:2).

EXAMPLE B2

[0200] A mixture of4-(3-chlorophenyl)-6-[hydroxybis(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinolinonehydrochloride (1:2)(obtained in Example B1)(0.00141 mol), iodomethane(0.00282 mol) and benzyltriethylammonium chloride (0.000141 mol) insodium hydroxide (20 ml) and THF (20 ml) was stirred at room temperatureovernight, then extracted with EtOAc and decanted. The organic layer wasdried (MgSO₄), filtered and the solvent was evaporated till dryness. Theresidue (1.7 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. The residue was dissolved in2-propanone and converted into the ethanedioic acid salt (1:2). Theprecipitate was filtered off and dried, yielding 0.16 g (16.5%) of4-(3-chlorophenyl)-6-[hydroxybis(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate (1:2) hydrate (1:3), mp=154° C.

EXAMPLE B3

[0201] NaH 80% in oil (0.008 mol) was added under N₂ flow to a mixtureof intermediate (11) (0.0067 mol) in N,N-dimethylformamide (30 ml),while cooling on ice. The mixture was stirred at this temperature for 1hour. lodomethane (0.008 mol) was added dropwise. The mixture wasstirred at room temperature for 1 hour, hydrolyzed and extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated till dryness. The residue (3 g) was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH95/5/0.1; 15-40 μm). Two pure fractions were collected and the solventwas evaporated,. yielding 0.8 g F1 and 1.2 g F2 (38.7%). F1 wasdissolved in 2:-propanone and converted into the ethanedioic acid salt(1:1). The precipitate was filtered off and dried, yielding 0.7 g(17.9%) of(±)-4-(3-chlorophenyl)-6-[methoxy(1-methyl-1-imidazol-5-yl)-2-thiazolylmethyl]-1-methyl-2(1H)-quinolinone ethanedioate (1:1) monohydratemp.246° C. F2 was crystallized from CH₃CN, 2-propanone and DIPE. Theprecipitate was filtered off and dried, yielding 0.75 g (24%) of(±)-4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-2-thiazolylmethyl]-1-methyl-2(1H)-quinolinone,mp. 246° C.

EXAMPLE B4

[0202] a) A mixture of intermediate (20)(0.0245 mol),2-phenyl-1H-imidazole (0.0368 mol) and K₂CO₃ (0.0735 mol) inacetonitrile (150n) was stirred at 60° C. The solvent was evaporatedtill dryness. The residue was taken up in DCM and water. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0. 1;15-40 μm). The pure fractions were collected and the solvent wasevaporated, yielding 0.8 g (5.1%) of ethyl4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(2-phenyl-1H-imidazol-1-yl)(4-phenyl-2-thiazolyl)methyl]-3-quinolinecarboxylate.

[0203] b) A solution of ethyl4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(2-phenyl-1H-imidazol-1-yl)(4-phenyl-2-thiazolyl)methyl]-3-quinolinecarboxylate,obtained in stage a)(0.00124 mol) in THF (15 ml) was added dropwise at5° C. under N₂ flow to a mixture of LiAlH₄ (0.0049 mol) in THF(10 ml).The mixture was stirred at 5° C. for 1 hour and hydrolyzed. EtOAc wasadded. The mixture was filtered over celite and the filtrate wasdecanted. The organic layer was dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (0.7 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue (0.5 g) was converted into the ethanedioic acid salt (1:1) in2-propanone/CH₃CN/DIPE. The precipitate was filtered off and dried,yielding: 0.43 g (50%) of4-(3-chlorophenyl)-3-(hydroxymethyl)-6-[(2-phenyl-1H-imidazol-1-yl)(4-phenyl-2-thiazolyl)methyl]-2(1H)-quinolinoneethanedioate, mp. 149° C.

EXAMPLE B5

[0204] Benzimidazole (0.0078 mol) was added to a mixture of intermediate(23)(0.0026 mol) in acetonitrile (20 ml). The mixture was stirred andrefluxed for 6 hours, taken up in CH₂Cl₂/H₂O. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated tilldryness. The residue (0.84 g) was purified by column chromatography oversilica gel (eluent: toluene/iPrOH/NH₄OH 65/25/0.5 to 50/50/2; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue (0.6 g, 48%) was crystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 0.58 g (46%) of6-[(1H-benzimidazol-1-yl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,mp.>260° C.

EXAMPLE B6

[0205] BuLi 1.6 M (20.6 ml) was added dropwise at −70° C. under N₂ flowto a mixture of 1-methyl-1H-imidazole (0.033 mol) in THF(60 ml). Themixture was stirred at −70° C. for 30 min. chlorotriethyl-silane (0.033mol) was added. The mixture was brought slowly to 10° C. and cooledagain to −70° C. BuLi 1.6 M (20.6 ml) was added dropwise. The mixturewas stirred at −70° C. for 1 hour, brought to −15° C. and cooled againto −70° C. A suspension of (intermediate 27)(0.022 mol) in THF(80 ml)was added dropwise. The mixture was stirred at −70° C. for 30 min, thenbrought to room temperature, hydrolized, extracted with EtOAc anddecanted. The organic layer was dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (13 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2;20-45 μm). Two pure fractions were collected and their solvents wereevaporated. The residue was crystallized from CH₃CN and diethyl ether.The precipitate was filtered off and dried. Yielding: 1.2 g (12.2%) of(±)-4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,melting point 248° C.

EXAMPLE B7

[0206] A mixture of 1-methyl-1H-imidazole (0.0054 mol) in THF(10 ml) wascooled to −70° C. BuLi 1.6 M (3.4 ml) was added dropwise and the mixturestood at −70° C. for 30 min. Chlorotriethylsilane (0.0054 mol) wasadded. The mixture was allowed to warm to 10° C. and then cooled to −70°C. BuLi 1.6 M (3.4 ml) was added dropwise. The mixture stood at −70° C.for 1 hour, brought quickly to −15° C. and cooled to −70° C. THF(20 ml)and then intermediate 29)(0.0045 mol) were added. The mixture wasallowed to warm to room temperature, stirred at room temperatureovernight, stirred and refluxed for 24 hours, then hydrolized andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated till dryness. The residue (2.7g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanone/DIPE. The precipitate was filtered off and dried,yielding 0.6 g (28%) of4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-2-yl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,melting point 130° C.

EXAMPLE B8

[0207] a) BuLi 1.6 M (20.6 ml) was added dropwise at −70° C. under N₂flow to a mixture of 1-methyl-1H-imidazole (0.033 mol) in THF(60 ml).The mixture was stirred at −70° C. for 30 min. chlorotriethyl-silane(0.033 mol) was added. The mixture was brought slowly to 10° C. andcooled again to −70° C. BuLi 1.6 M (20.6 ml) was added dropwise. Themixture was stirred at −70° C. for 1 hour, brought to −15° C. and cooledagain to −70° C. A suspension of intermediate 27 (0.022 mol) in THF(80ml) was added dropwise. The mixture was stirred at −70° C. for 30 min,then brought to room temperature, hydrolized, extracted with EtOAc anddecanted. The organic layer was dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (13 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2;20-45 μm). One pure fraction was collected and the solvent evaporated.The residue was crystallized from CH₃CN and diethyl ether. Theprecipitate was filtered off and dried, yielding 1.2 g (12.2%) of4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,melting point 248° C.

[0208] b)4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone(obtained in stage a)(0.0045 mol) was added to thionyl chloride (30 ml)at 5° C. The mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated till dryness. The product was used withoutfurther purification, yielding (quant.) of6-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

[0209] c) A mixture of6-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(obtained in stage b)(0.0045 mol) in THF (30 ml) was cooled to 5° C.2-Propanol-NH₃ saturated (30 ml) was added dropwise quickly. The mixturewas stirred at room temperature for 1 hour. The solvent was evaporatedtill dryness. The residue was taken up in DCM and water and the mixturewas decanted. The organic layer was dried (MgSO₄), filtered and thesolvent was evaporated till dryness. The residue (2.2 g) was purified bycolumn chromatography over silica gel (eluent: toluene/2-propanol/NH₄OH85/13/1; 15-40 μm). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃CN and DIPE. Theprecipitate was filtered off and dried, yielding 0.55 g (27.5%) of(±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,melting point 197° C.

[0210] The following compounds were prepared analogous to the one of theabove examples (the example number analogous to which they were preparedis indicated between square brackets after the compound number). Massspectral data (ms) is given for MH⁺ peaks, determined by electron sprayionisation (ESI).

ethanedioate; [B5], [B3], MS(MH+): 462, 464 mp. 195° C.

[B5], mp. 86° C. [B3], mp > 260° C.

[B5], MS: 494, 496 [B5], MS: 557, 559 [B5], MS: 508, 510

[B5]; MS(MH⁺): 480, 482 [B5]; MS(MH⁺): 457, 459 [B5]; MS(MH⁺): 505, 507

[B5]; MS(MH⁺): 505, 507 [B5]; MS(MH⁺): 480, 482 [B5]; MS(MH⁺): 430, 432

[B5]; MS(MH⁺): 443, 445

[0211] C. Pharmacological Example.

EXAMPLE C.1

[0212] “In Vitro Assay for Inhibition of Farnesyl Protein Transferase”:

[0213] An in vitro assay for inhibition of farnesyl transferase wasperformed essentially as described in WO 98/40383, pages 33-34.

EXAMPLE C.2

[0214] “Ras-Transformed Cell Phenotype Reversion Assay”.

[0215] The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3

[0216] “Farnesyl Protein Transferase Inhibitor Secondary Tumor Model”.

[0217] The farnesyl protein transferase inhibitor secondary tumor modelwas used as described in WO 98/40383, page 37.

[0218] D. Composition Example: Film-coated Tablets

[0219] Preparation of Tablet Core

[0220] A mixture of 100 g of a compound of formula (I), 570 g lactoseand 200 g starch is mixed well and thereafter humidified with a solutionof 5 g sodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about200 ml of water. The wet powder mixture is sieved, dried and sievedagain. Then there are added 100 g microcrystalline cellulose and 15 ghydrogenated vegetable oil. The whole is mixed well and compressed intotablets, giving 10.000 tablets, each comprising 10 mg of a compound offormula (I).

[0221] Coating

[0222] To a solution of 10 g methyl cellulose in 75 ml of denaturatedethanol there is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein r is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or3; >Y¹—Y² is a trivalent radical of formula>C═CR⁹—  (y-2)>CH—CHR⁹—  (y-4)wherein R⁹ is hydrogen, halo, cyano,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,halocarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl or a group offormula —NR²²R²³, —C₁₋₆alkyl-NR²²R²³, —C₂₋₆alkenyl-NR R²²R²³, —CONR²²R²or —NR²—C₁₋₆alkyl-NR²²R²³; p is 0 to 5; R²⁰ and R²¹ are independentlyhydrogen or C₁₋₆alkyl and are independently defined for each iterationof p in excess of 1; R²² and R²³ are independently hydrogen, C₁₋₆ alkylor —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or together with the adjacentnitrogen atom form a 5- or 6-membered heterocyclic ring optionallycontaining one, two or three further heteroatoms selected from oxygen,nitrogen or sulphur and optionally substituted by one or twosubstituents each independently selected from halo, hydroxy, cyano,nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- ordi-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkylsulfonylamino, oxime, or phenyl; R¹ is azido, hydroxy, halo,cyano, nitro, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴S C₁₋₆alkyl, trihalomethyl,arylC₁₋₆alkyl, Het²C₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³,—C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²COC₁₋₆alkyl,—C₁₋₆alkylNR²²COAlkAr², —C₁₋₆alkylNR²²COAr²,C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³, trihalomethoxy,arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio, C₂₋₆alkenyl,cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³, hydroxycarbonylC₂₋₆alkenyl,C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl,hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,—CONR²²R²³, —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het²,—CONR²²—C₁₋₆alkyl-Ar², —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl, —NRR²²R²³, —OC(O)R²⁴, —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵NR²⁴C(O) NR²²R²³—NR²⁴SO₂R²⁵,—NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵, —C(NR²⁶R²⁷)═NR²⁸; —Sn(R²⁴)₃,—SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵,aryloxy, Het²-oxy, or a group offormula —Z, —CO—Z or —CO—NR^(Y)—Zin which R^(y) is hydrogen or C₁₋₄alkyland Z is phenyl or a 5- or 6-membered heterocyclic ring containing oneor more heteroatoms selected from oxygen, sulphur and nitrogen, thephenyl or heterocyclic ring being optionally substituted by one or twosubstituents each independently selected from halo, cyano,hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio, hydroxy, —NR²²R²³,C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyloxy orphenyl; or two R¹ substituents adjacent to one another on the phenylring may form together a bivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O—CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-5)—CH═CH—CH═CH—  (a-6)R²⁴and R²⁵ are independently hydrogen, C₁₋₆ alkyl,—(CR₂₀R₂₁)_(p)—C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl; R²⁶, R²⁷ and R²⁸ areindependently hydrogen and C₁₋₆alkyl or C(O) C₁₋₆alkyl; R² is a mono- orbi-cyclic heterocyclic ring containing either at least one oxygenheteroatom or two or more heteroatoms selected from oxygen, sulphur andnitrogen, each such ring being optionally substituted by one or twosubstituents each independently selected from halo, cyano, hydroxy,nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³ C₁₋₆alkyloxy, OCF₃,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime, phenyl or benzyl; R³ is hydrogen, halo,cyano, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,arylC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl,hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³,arylC₁₋₆alkyl, Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenylNR²²R²³,C₂₋₆alkynyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or aradical of formula —O—R¹⁰  (b-1)—S—R¹⁰  (b-2) or—NR¹¹R¹²  (b-3) whereinR¹⁰ is hydrogen, C₁₋₆alkyl, —(CR² R²¹)_(p)—C₃₋₁₀cycloalkyl,arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl, agroup of formula —NR²²R²³R or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or aradical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl or arylC₁₋₆alkyl; R¹² is hydrogen, hydroxy, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group offormula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl,arylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₆alkylcarbonyl,aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkylmoiety may optionally be substituted by one or more substituentsindependently selected from aryl andC₁₋₆alkyloxycarbonyl substiuents;aminocarbonylcarbonyl, mono-ordi(C₁₋di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula-Alk-OR¹ ³ or Alk-NR¹⁴R¹⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ ishydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl , C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl;R¹⁴ is hydrogen,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl , C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkylcarbonyl, aryl or arylC₁₋₆alkyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, a group offormula —NR²²R²³, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl or aryl, R¹⁷ ishydrogen, C₁₋₆alkyl, —(Cr²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl, trifluoromethyl,trifluoromethylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono- or di (C₁₋₆alkyl)aminosulphonyl or—C₁₋₆alkylP(O)OR²⁴OR²⁵; R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³or —CONR²²R²³; R⁶ishydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,—C₁₋₆alkylCO₂R²⁴, aninocarbonylC₁₋₆alkyl or —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂,R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴, —C₁₋₆alkyl-SR²⁴,—C₁₋₆alkylCONR²²—C₁₋₆alky-NR²²R²³, —C₁₋₆alkylCONR —Cl alkyl-Het²,—C₁₋₆alkylCONR²²—C₁₋₆alkyl-Ar², —C₁₋₆alkyl CONR²²-Het²,—C₁₋₆alkylCONR²²Ar², —C₁₋₆alkylCONR²²—O—C₁₋₆alkyl,—C₁₋₆alkylCONR²²—C₁₋₆alkenyl, -Alk-Ar or -AlkHet²; R⁷ is oxygen orsulphur; Ar² is phenyl, naphthyl or phenyl or naphthyl substituted byone to five substituents each independently selected from halo, hydroxy,cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy,OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent substituent offormula —O—CH₂—O— or —O—CH₂—CH₂—O—; Het² is a mono- or bi-cyclicheterocyclic ring containing one or more heteroatoms selected fromoxygen, sulphur and nitrogen and optionally substituted by one or twosubstituents each independently selected from halo, hydroxy, cyano,nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime or phenyl.
 2. A compound according toclaim 1 in which r is 0, 1 or 2; t is 0 or 1; >Y¹Y²— is a trivalentradical of formula >C═CR⁹—  (y-2) wherein R⁹ is hydrogen, cyano, halo,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl; R¹ ishalo, C₁alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, C₁₋₆alkylthio,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, or —CH═NOR²⁵; or twoR¹ substituents adjacent to one another on the phenyl ring mayindependently form together a bivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2) R² is a 5- or 6-membered monocyclicheterocyclic ring containing either one oxygen heteroatom or two orthree heteroatoms selected from oxygen, sulphur and or nitrogen or a 9-or 10-membered bicyclic heterocyclic ring containing either one oxygenheteroatom or two or three heteroatoms selected from oxygen, sulphur andor nitrogen. R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,—C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl, —C₂₋₆alkenyl NR²²R²³, or -Het²; or agroup of formula —O—R¹⁰  (b-1)—NR¹¹R²  (b-3) wherein R¹⁰ is hydrogen,C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula-Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen or C₁₋₆alkyl; R¹² ishydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, aminocarbonyl, or a radical of formula-Alk-OR¹³ or Alk-NR¹⁴R⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ is hydrogen,C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁴ is hydrogen, C₁₋₆alkyl,or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁵ is hydrogen or C₁₋₆alkyl; R⁴ is aradical of formula (c-2) wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl, R¹⁷is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₀cycloalkyl,C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl; R⁵ is cyano, halo, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl: R⁶ is hydrogen,C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkyl-C(O)NR²²R²³, -Alk-Ar² R⁷ isoxygen; Het² is a 5- or 6-membered monocyclic heterocyclic ringcontaining one, two or three heteroatoms selected from oxygen, sulphuror nitrogen for example pyrrolidinyl, imidazolyl, triazolyl, pyridyl,pyrimidinyl, furyl, morpholinyl, piperazinyl, piperidinyl, thiophenyl,thiazolyl or oxazolyl, or a 9- or 10-membered bicyclic heterocyclic ringespecially one in which a benzene ring is fused to a heterocyclic ringcontaining one, two or three heteroatoms selected from oxygen, sulphuror nitrogen for example indolyl, quinolinyl, benzimidazolyl,benzotriazolyl, benzoxazolyl, benzothiazolyl or benzodioxolanyl.
 3. Acompound according to claim 1 in which >Y¹—Y²— is a trivalent radical offormula (y-2), wherein R⁹ is hydrogen, halo, C₁₋₄alkyl, hydroxycarbonyl,or C₁₋₄alkyloxycarbonyl; r is 0, 1 or 2; t is 0; R¹ is halo, C₁₋₆alkylor two R¹ substituents ortho to one another on the phenyl ring mayindependently form together a bivalent radical of formula (a-1); R² is a5- or 6-membered monocyclic heterocyclic ring containing one oxygenheteroatom or two heteroatoms selected from oxygen, sulphur or nitrogenor a 9- or 10-membered bicyclic heterocyclic ring in which a benzenering is fused to a heterocyclic ring containing either at least oneoxygen heteroatom or two or heteroatoms selected from oxygen, sulphur ornitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl; R³is Het² or a group of formula (b-1) or (b-3) wherein R¹⁰ is hydrogen ora group of formula -Alk-OR¹³. R¹¹ is hydrogen; R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl; Alk is C₁₋₆alkanediyl and R¹³ ishydrogen; R⁴ is a group of formula (c-2) wherein R¹⁶ is hydrogen, haloor mono- or di(C₁₋₄alkyl)amino; R¹⁷ is hydrogen or C₁₋₆alkyl; R⁶ is—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴,aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet² or C₁₋₆alkyl; R⁷ is oxygen;aryl is phenyl.
 4. A compound according to claim 1 in which >Y¹—Y² is atrivalent radical of formula (y-2), r is 0 or 1, t is 0, R¹ is halo,C₍₁₋₄₎alkyl or forms a bivalent radical of formula (a-1), R² is a 5- or6-membered monocyclic heterocyclic ring containing either one oxygenheteroatom or two heteroatoms selected from oxygen, sulphur or nitrogenor a 9- or 10-membered bicyclic heterocyclic ring in which a benzenering is fused to a heterocyclic ring containing either one oxygenheteroatom or two or heteroatoms selected from oxygen, sulphur ornitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl; R³is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-2), R¹⁰ is hydrogen or -Alk-OR¹³, R¹¹ is hydrogen and R¹² ishydrogen or C₁-C₁₋₆alkylcarbonyl and R¹³ is hydrogen; R⁶ is C₁₋₆alkyl,—CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴ (R²⁴═H,Et),aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and R⁷ is oxygen.
 5. Acompound according to claim 1 in which >Y¹—Y² is a trivalent radical offormula (y-2), r is 0 or 1, s is 1, t is 0, R¹ is halo, preferablychloro and most preferably 3-chloro, R² is a furyl, diazolyl, oxazolylor benzodiazolyl, benzotriazolyl group, optionally substituted by halopreferably chloro, cyano, C₁₋₆alkyl, preferably methyl or aryl; R³ ishydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-2), R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹²is hydrogen R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²; R⁷is oxygen.
 6. A compound according to claim 1 in which >Y¹—Y² is atrivalent radical of formula (y-2), r is 1, t is 0, R¹ is halo,preferably chloro, and most preferably 3-chloro, R² is a 3-furyl,imidazol-1-yl,, benzimidazol-1-yl group optionally substituted by halopreferably chloro, cyano, C₁₋₆alkyl, preferably methyl or phenyl; R³ isa radical of formula (b-1) or (b-3), R⁴ is a radical of formula (c-2),R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy,R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or -alkylAr²; and R⁷ is oxygen. 7.A compound according to claim 1 selected from(±)-4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,(±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,6-[1H-benzimidazol-1-yl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,6-[1H-1,2,3-benzotriazol-1-yl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,4-(3-chlorophenyl)-1-methyl-6-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-2(1H)-quinolinone,4-(3-chlorophenyl)-6-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,4-(3-chlorophenyl)-1-methyl-6-[(1-methyl-1H-imidazol-5-yl)(4-methyl-1H-imidazol-1-yl)methyl]-2(1H)-quinolinone,and their pharmaceutically acceptable salts.
 8. A process for thepreparation of a compound according to claim 1 which comprises: a)cyclising a compound of formula (II)

with a reagent serving to form a compound of formula (I) in which R⁶ ishydrogen and R⁷ is oxygen; b) reacting a compound of formula (III):

in which W¹ represents a replaceable or reactive group, with a reagentserving either to react with or replace the W¹ group in compound (III)to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is anoxygen or sulphur group; or c) reacting a compound of formula (IV):

in which W² is a leaving group and W³ is the group R² above or W² is thegroup R⁴ above and W³ is a leaving group, with a reagent serving toreplace the leaving group W² or W³ with the respective R⁴ or R² group;or d) reacting a compound of formula (V):

(in which R^(x) is the group R² or R⁴ above) with a heterocyclic reagentof formula R^(4a)L (when R^(x) is R²) or R^(2a)L (when R^(x) is R⁴) inwhich L is a leaving atom or group and R^(2a) is R² or a precursor grouptherefor and R^(4a) is R⁴ or a precursor group therefor, and ifrequired, converting said precursor group to the parent group, to form acompound of formula (I) in which R³ is hydroxy; e) reacting a compoundof formula (VI):

with a reagent serving to convert the said compound (VI) to a compoundof formula (I) in which R⁶ is hydrogen and R⁷ is oxygen; and optionallyeffecting one or more of the following conversions in any desired order:(i) converting a compound of formula (I) into a different compound offormula (I) (ii) converting a compound of formula (I) in to apharmaceutically acceptable salt or N-oxide thereof; (iii) converting apharmaceutically acceptable salt or N-oxide of a compound of formula (I)into the parent compound of formula (I); (iv) preparing a stereochemicalisomeric form of a compound of formula (I) or a pharmaceuticallyacceptable salt or N-oxide thereof.
 9. A compound according to any ofclaims 1 to 7 for use as a medicine.
 10. A compound according to claim 9for use in inhibiting tumor growth.
 11. A method for inhibiting tumorgrowth by administering an effective amount of a compound according toclaim 1 to a subject, in need of such treatment.